Computational Simulations of PROTAC as a BRD4 Inhibitor in Neuroblastoma

Abstract

Neuroblastoma (NB) is the most common cancer of nerve tissue in babies. The oncogene MYCN gets amplified in the disease, which can be inhibited by targeting the BRD4 protein. PROTAC, a protein degradation tool, is an emerging therapeutic strategy that targets disease-causing proteins. Two proteins are the subject of the current study project: BRD4 protein and E3 ubiquitin (E3) ligase protein. The BRD4 protein is crucial for controlling genes and maintaining cell viability; when it malfunctions, neuroblastoma can result. However, the BRD4 protein's activity can be inhibited by the E3 protein, which also functions as a cancer suppressor. To destroy the BRD4 protein, the E3 protein should come into proximity to each other. We hypothesize that the aptamers used in this study will bind strongly at the interface between the BRD4 and E3 ligase protein. This is made possible by a substance called PROTAC, which binds to the E3 and BRD4 proteins, drawing them together to form the BRD4-PROTAC-E3 complex. In the present study, molecular docking was utilized to understand the BRD4-PROTAC-E3 interactions, and based on this knowledge, we designed 10 new PROTACs and calculated their medicinal properties. Based on our analysis, Aptamer II formed strong interactions with both the proteins. The discovery of new PROTACs will facilitate the computer-aided design of robust, cost-effective, and minimally side-effecting PROTACs against cancer.

Keywords: Neuroblastoma (NB), BRD4, PROTAC.